Article

Osteolineage niche cells initiate hematopoietic stem cell mobilization (Retracted article. See vol. 119, pg. 1793, 2012)

Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Department of Stem Cell and Regenerative Biology, Harvard University, and Harvard Stem Cell Institute, Boston, MA 02215, USA.
Blood (Impact Factor: 9.78). 06/2008; 112(3):519-31. DOI: 10.1182/blood-2008-01-133710
Source: PubMed

ABSTRACT Recent studies have implicated bone-lining osteoblasts as important regulators of hematopoietic stem cell (HSC) self-renewal and differentiation; however, because much of the evidence supporting this notion derives from indirect in vivo experiments, which are unavoidably complicated by the presence of other cell types within the complex bone marrow milieu, the sufficiency of osteoblasts in modulating HSC activity has remained controversial. To address this, we prospectively isolated mouse osteoblasts, using a novel flow cytometry-based approach, and directly tested their activity as HSC niche cells and their role in cyclophosphamide/granulocyte colony-stimulating factor (G-CSF)-induced HSC proliferation and mobilization. We found that osteoblasts expand rapidly after cyclophosphamide/G-CSF treatment and exhibit phenotypic and functional changes that directly influence HSC proliferation and maintenance of reconstituting potential. Effects of mobilization on osteoblast number and function depend on the function of ataxia telangiectasia mutated (ATM), the product of the Atm gene, demonstrating a new role for ATM in stem cell niche activity. These studies demonstrate that signals from osteoblasts can directly initiate and modulate HSC proliferation in the context of mobilization. This work also establishes that direct interaction with osteolineage niche cells, in the absence of additional environmental inputs, is sufficient to modulate stem cell activity.

0 Followers
 · 
125 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by clonal proliferation of stem cell-like blasts in bone marrow; however, their unique cellular interaction within the bone marrow microenvironment and its functional significance remain unclear. Here, we assessed the bone marrow microenvironment of AML patients and demonstrate that the leukemia stem cells induce a change in the transcriptional programming of the normal mesenchymal stromal cells. The modified leukemic niche alters the expressions of cross-talk molecules (i.e., CXCL-12 and Jagged-1) in mesenchymal stromal cells to provide a distinct cross-talk between normal and leukemia cells, selectively suppressing normal primitive hematopoietic cells while supporting leukemogenesis and chemoresistance. Of note, AML patients exhibited distinct heterogeneity in the alteration of mesenchymal stroma in bone marrow. The distinct pattern of stromal changes in leukemic bone marrow at initial diagnosis was associated with a heterogeneous post-treatment clinical course with respect to the maintenance of complete remission for 5-8 years and early or late relapse. Thus, remodeling of mesenchymal niche by leukemia cells is an intrinsic self-reinforcing process of leukemogenesis that can be a parameter for the heterogeneity in the clinical course of leukemia and hence serve as a potential prognostic factor. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 03/2015; 75(11). DOI:10.1158/0008-5472.CAN-14-3379 · 9.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Using a mouse model, Iron Overload (IO) induced bone marrow microenvironment injury was investigated, focusing on the involvement of reactive oxygen species (ROS). Mice were intraperitoneally injected with iron dextran (12.5, 25, or 50mg) every three days for two, four, and six week durations. Deferasirox(DFX)125mg/ml and N-acetyl-L-cysteine (NAC) 40mM were co-administered. Then, bone marrow derived mesenchymal stem cells (BM-MSCs) were isolated and assessed for proliferation and differentiation ability, as well as related gene changes. Immunohistochemical analysis assessed the expression of haematopoietic chemokines. Supporting functions of BM-MSCs were studied by co-culture system. In IO condition (25mg/ml for 4 weeks), BM-MSCs exhibited proliferation deficiencies and unbalanced osteogenic/adipogenic differentiation. The IO BM-MSCs showed a longer double time (2.07±0.14 days) than control (1.03±0.07 days) (P<0.05). The immunohistochemical analysis demonstrated that chemokine stromal cell-derived factor-1, stem cell factor -1, and vascular endothelial growth factor-1 expression were decreased. The co-cultured system demonstrated that bone marrow mononuclear cells (BMMNCs) co-cultured with IO BM-MSCs had decreased colony forming unit (CFU) count (p<0.01), which indicates IO could lead to decreased hematopoietic supporting functions of BM-MSCs. This effect was associated with elevated phosphatidylinositol 3 kinase (PI3K) and reduced of Forkhead box protein O3 (FOXO3) mRNA expression, which could induce the generation of ROS. Results also demonstrated that NAC or DFX treatment could partially attenuate cell injury and inhibit signaling pathway striggered by IO. These results demonstrated that IO can impair the bone marrow microenvironment, including the quantity and quality of BM-MSCs.
    PLoS ONE 03/2015; 10(3):e0120219. DOI:10.1371/journal.pone.0120219 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Stem cells have an essential role in tissue homeostasis, repair, and regeneration of a tissue or organ. Stem cells are immature cells having unlimited ability of self-renewal and capacity to differentiate into specialized cell types. Proper regulation of these dual properties is critical in animal development, growth control, and reproduction. Accumulating evidences suggest that stem cell behavior is regulated by both extracellular signals from the niche cells and intrinsic signal within stem cells. Using diverse model systems, tremendous work has been done to understand how niche control the stem cell self-renewal and differentiation. This review presents the progress made in stem cell niche field in germline and somatic stem cells in lower organism and mammals. The knowledge gained by studying the stem cells and its niches in diverse model organisms and the molecular mechanisms regulate their behavior are vital in understanding tissue homeostasis, regeneration, aging and cancer in humans.
    Current Medicinal Chemistry 09/2012; DOI:10.2174/092986712804485917 · 3.72 Impact Factor

Preview